Minocycline Therapy for Lung Scarring in Patients With Idiopathic Pulmonary Fibrosis - a Pilot Study

Pulmonary fibrosis is essentially scarring in the lungs. Some types (DIP, NSIP) most often respond to therapy. Others like UIP (usual interstitial pneumonitis) rarely respond. UIP frequently progresses and has a poor prognosis with a survival of three to five years. In UIP, most often the cause cannot be determined and is therefore called Idiopathic Pulmonary Fibrosis (IPF). A prevalence rate of 27-29 cases/100,000 has been reported that may even be as high as 250 cases/100,000 in individuals 75 years of age.

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal pulmonary disorder. Conventional treatment with immunosuppressive therapy has been disappointing, with a median survival of <40% at five years after diagnosis. Moreover, this therapy may lead to premature deaths that are a result of immunosuppression and susceptibility to infectious disease. Another problem related to IPF, is that we have an incomplete picture of the natural history of the pathogenesis of this disorder. Clearly, new strategies for therapy are necessary.

Published evidence suggests that less than 20% of patients with IPF respond to corticosteroids (prednisone). In patients that fail steroids, immunosuppressant drugs such as azathioprine or cyclophosphamide are used. An international consensus statement recommends both steroids and azathioprine or cyclophosphamide from the onset of treatment. Unfortunately a large number of trials have shown little or no effect of these drugs on the progression of disease. There are currently no FDA approved drugs for the treatment of IPF.

Laboratory findings establish that human specimens of Interstitial Lung Diseases including IPF demonstrate an impalance in expression of proteins (Th2 Cytokines, CC Chemokines, and CXC Chemokines). When these protein levels are in excess or low, they alter the normal lung mechanism, causing angiogenesis (abnormal blood vessel formation), inflammation, scar tissue formation and impaired immunity of the patient. We hope to establish that the efficacy of anti-angiogenetic agent as an add on therapy for IPF patients, will prove to bring stabilization or improvement.

Minocycline has been shown to inhibit angiogenesis (new abnormal blood vessel formation) and thus affect the fibrotic process (prevent scar tissue formation). Laboratory and animal studies support a potential therapeutic role for Minocycline in IPF.

Minocycline is a semi synthetic derivative of tetracycline. It was first marketed as an antibiotic in 1972. Clinical trials of minocycline have mainly been performed in sexually transmissible diseases and in acne. Minocycline is also used to treat several other diseases such as nocardiasis, mycobacteriosis, leprosy, lyme disease, pyoderma gangrenosum, autoimmune bullous dermatitis, carteaud disease, and prurigo. The usual side effects of minocycline are: lightheadedness, dizziness, or vertigo and pigmentation.

We will investigate genetic, molecular, cellular, whole animal models, and human specimens from patients with fibrotic lung disease to test our prediction: The pathogenesis of pulmonary fibrosis (lung scarring) is due to "multiple hits" that causes an inbalance of certain mediators (proteins) that are responsible for abnormal blood vessel formation, scar tissue formation (with and without inflammation inside the lungs) and impaired immunity of the patient. Each of the 3 projects in this proposal have a direct link to other projects and clinical core. The SCOR clinical core will identify and enroll patients with Interstitial Lung diseases (ILD), including IPF. The clinical core will collect clinical data, as well as obtain fluids from lung washings and human lung tissue specimens. Each project will use human specimens as indicated in each of their specific aims to correlate their findings with response to therapy.